White blood cells, mainly phagocytes [neutrophils (PMN) and macrophages (M&)], control local acute inflammation that is ideally self-limited. Little has been done to address the physiologic mechanisms that govern resolution of inflammation. The overall goal of this proposal is to establish novel controllers in endogenous resolution circuits because it is now clear that uncontrolled inflammation is associated with many widely occurring diseases including cardiovascular, neurologic, and classic inflammatory disorders. Resolution of acute inflammation was believed to be passive. New evidence from the PI's laboratory demonstrates that resolution is an active process with the identification of a new genus of specialized pro-resolving mediators (SPM). The genus includes resolvins (Rv), protectins (PD) and their aspirin-triggered (AT) forms biosynthesized from essential omega-3 fatty acids (n-3 EFA). SPM are potent stereoselective agonists that are anti- inflammatory, pro-resolving and stimulate host anti-microbial mechanisms. This proposal focuses on systematic elucidation of resolution components activated in self-limited inflammation using an unbiased mediator- lipidomics approach together with exudate tracking of leukocytes and chemical mediators. In work in progress, we found Rv (i.e. RvD1) and a new family of mediators coined maresins (MaR) that regulate both PMN and M& responses critical for resolution. Here we shall test the hypothesis that Local production of endogenous anti-inflammatory and pro-resolving mediators by exudate phagocytes is required for timely resolution. Newly identified SPM temporally govern PMN and M& responses via receptors and miR required for resolution and return to homeostasis. To address this, 4 specific aims are proposed to establish 1) the temporal relationships between eicosanoids and SPM produced in resolution versus non-resolving inflammation in murine exudates; 2) identify novel SPM pro-resolving receptors; 3) validate SPM-specific pro-resolving receptor axis and 4) characterize SPM driven microRNA and their targets that regulate resolution. Results from these studies will affect this scientific area and patient care by obtaining evidence for endogenous anti-inflammatory and pro-resolving mechanisms. Since new anti-inflammatories that are not immunosuppressive are needed, our long-term goals include providing novel molecules, i.e. SPM, and tools to clinicians that activate resolution to improve current treatments for diseases characterized by ungoverned inflammation. ) PUBLIC HEALTH RELEVANCE: Since uncontrolled inflammation underlies many widely occurring diseases, this research is relevant to public health because the proposed studies focus on characterizing the body's own mechanisms that govern the resolution of acute inflammation.